Not applicable.
Sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress chemically-initiated carcinogenesis. This action has been attributed to the isoprenoid-mediated induction of detoxifying activities and to the antioxidant activity of some isoprenoids. Neither action explains the potent impact isoprenoids have on the promotion/progression stage of chemically-initiated carcinogenesis and on the growth of chemically established and implanted tumors (reviewed by Elson, 1995; Elson and Yu, 1994). Isoprenoids differ substantially in the impact they have on tumor growth. Isoprenoids suppress, via post-transcriptional actions (Correll, et al., 1994; Parker, et al., 1993; D. M. Peffley and A. K. Gayen, personal communication), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, the activity deemed to be rate-limiting for the synthesis of cholesterol. The statins are competitive inhibitors of HMG-CoA reductase. Correlations between the late stage tumor-suppressive potency of diverse isoprenoids and their impact on HMG-CoA reductase activity approach unity. The reductase activity of tumors differs from that of liver in being resistant to sterol feedback regulation. The tumor activity however retains high sensitivity to post-transcriptional regulation as triggered by diverse isoprenoids. As a consequence of the isoprenoid-mediated suppression of HMG-CoA reductase activity the pools of mevalonate pathway intermediates become limiting for the post-translational processing of growth-associated proteins (reviewed by Elson, 1995; Elson and Yu, 1994).
One recent review presented a list of structurally diverse isoprenoids with varying capacity to suppress mevalonate synthesis (Elson, 1995).
In one embodiment, the present invention is a method for inhibiting tumor cell growth. The method comprises treating the cell with a combination of at least two products of the mevalonate pathway selected from the group consisting of statins, ionones and tocotrienols.
In one preferred embodiment, the ionone is selected from the group consisting of xcex2-ionone; 6-10-dimethyl-undec-3,5-ene-2,9-dione; 6,10-dimethyl-9,10-epoxy-undec-3,5-ene-2-one; 9,10-diacetoxy-6,10-dimethyl-undec-3,5-ene-2-one; 6,10-dimethyl-9,10-diol-undec-3,5-ene-2-one and xcex1-ionone. Preferred tocotrienols include d-xcex3-tocotrienol, 2-desmethyltocotrienol, d-xcex4-tocotrienol and d-tocotrienol. Preferred statins include lovastatin, pravastatin, simvastatin and fluvastatin.
In another form, the present invention is a pharmaceutical composition for treating or preventing tumors comprising effective amounts of at least two agents selected from the group consisting of tocotrienols, statins and ionones.
It is an object of the present invention to prevent or reduce tumor growth and metastasis.
It is another object of the present invention to increase the duration of survival of a tumor patient following detection of tumor.
It is another object of the present invention to prevent tumor formation.
Other objects, advantages and features of the present invention will become apparent to one of skill in the art after review of the specification, claims and drawings.